Macrophages are prodigious secretory cells which can produce a number of molecules which can either potentiate or dampen immune responses (Nathan, J. Clin. Invest. 79:319-322, 1987). In response to infectious or inflammatory stimuli, macrophages can produce several proinflammatory molecules, including TNF.alpha., IL-1, IL-6 and IL-12 (Nathan, J. Clin. Invest. 79:319-322, 1987; Trinchieri et al., J. Leukocyte Biol. 59:505-511, 1996). These proinflammatory molecules are important for host defense, because experimentally infected animals deficient in these cytokines are invariably more susceptible to acute bacterial infections than are normal animals (Dalrymple et al., Infect. Immun. 63:2262-2268, 1995; Kincy-Cain et al., Infect. Immun. 64:1437-1440, 1996).
In many instances, macrophages can participate in the regulation of proinflammatory cytokines by the production of anti-inflammatory molecules. The secretion of glucocorticoids, TGF beta, and IL-10 by macrophages has been associated with anti-inflammatory responses (Tsunawaki et al., Nature 334:260-262, 1988; Bogdan et al., J. Exp. Med. 174:1549-1555, 1991; Kunkel et al., J. Biol. Chem. 263:5380-5384, 1988). These anti-inflammatory molecules have the potential to ameliorate the potentially deleterious effects of an overly aggressive immune response. Thus, the balance between the secretion of pro- and anti-inflammatory molecules by macrophages is a critical component of the acute phase response and has the potential to affect the adaptive immune response that subsequently develops.
Interleukin-10 (IL-10) is an 18 kDa cytokine produced by the Th2 subset of CD4+ helper cells. It is also produced by some activated B cells, by some Th1 cells (in humans), by activated macrophages, and by some non-lymphocytic cell types (e.g., keratinocytes). In contrast to IL-12, IL-10 has been associated with an inhibition of Th1-type immune responses. IL-10 has been shown to inhibit the production of Th1 cytokines and the proliferation of Th1 cells to antigen (Malefyt et al., J. Exp. Med. 174:915-924, 1991; Fiorentino et al., J. Immunol. 146:3444-3451, 1991). IL-10 inhibits IL-12 production by macrophages (D'Andrea et al., J. Exp. Med. 178:1041-1048, 1993), and the administration of exogenous IL-10 can diminish the toxicity of LPS (Howard et al., J. Exp. Med. 177:1205-1208, 1993; Berg et al., J. Clin. Invest. 96:2339-2347, 1995). IL-10 has been considered for the treatment of autoimmune diseases such as arthritis (Hart et al., Immunology 84:536-542, 1995) and colitis (Davidson et al., J. Exp. Med. 184:241-251, 1996), and recently for psoriasis
Mitogen-activated protein kinases (MAPKs) are members of conserved signal transduction pathways that activate transcription factors, translation factors and other target molecules in response to a variety of extracellular signals. In mammalian cells, three parallel MAPK pathways have been described. One MAPK pathway leads to the activation of the extracellular-signal-regulated kinase (ERK). Other signal transduction pathways leading to the activation of the cJun N-terminal kinase (JNK) and the p38 MAPK (for reviews, see Davis, Trends Biochem. Sci. 19:470-473 (1994); Cano and Mahadevan, Trends Biochem. Sci. 20:117-122(1995)). Previous studies conducted by the inventors (see U.S. Pat. No. 6,660,266) have indicated that ligation of the Fcγ receptor (FcR) on macrophages, in the presence of what would normally be an inflammatory stimulus, inhibits IL-12 release and induces high levels of IL-10 production. The inventors have since learned that FcR ligation may cause amplification the p38 and ERK MAPK pathways, and enhance Toll-like receptor (TLR)-induced IL-10 production, thus increasing the anti-inflammatory response potential of activated macrophages. This observation has lead to the discovery of a novel class of anti-inflammatory compounds that would work by enhancing ERK MAPK levels in cells such as leukocytes.